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Shutinoski B, Hakimi M, Harmsen IE, Lunn M, Rocha J, Lengacher N, Zhou YY, Khan J, Nguyen A, Hake-Volling Q, El-Kodsi D, Li J, Alikashani A, Beauchamp C, Majithia J, Coombs K, Shimshek D, Marcogliese PC, Park DS, Rioux JD, Philpott DJ, Woulfe JM, Hayley S, Sad S, Tomlinson JJ, Brown EG, Schlossmacher MG. Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner. Sci Transl Med. 2019 Sep 25;11(511) PubMed.
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Since LRRK2 plays a role in controlling the immune response of dendritic cells to Aspergillus, polymorphisms in this kinase could be responsible for a subpar immune response to fungi that permits CNS infection, leading to Parkinson's disease as the toxic effects of fungal-derived ochratoxin A and 1-octen-3-ol destroy dopaminergic neurons.
A defective immune response against fungi could be especially damaging if the fungi establishes long-term residence in the appendix, thereby producing a steady output of toxins which gradually damage CNS function. Findings that appendectomies reduce the risk of PD incidence in rural residents supports this argument, as rural residents are generally exposed to fungi more frequently than urban residents.
References:
Wong AY, Oikonomou V, Paolicelli G, De Luca A, Pariano M, Fric J, Tay HS, Ricciardi-Castagnoli P, Zelante T. Leucine-Rich Repeat Kinase 2 Controls the Ca2+/Nuclear Factor of Activated T Cells/IL-2 Pathway during Aspergillus Non-Canonical Autophagy in Dendritic Cells. Front Immunol. 2018;9:210. Epub 2018 Feb 8 PubMed.
Killinger BA, Madaj Z, Sikora JW, Rey N, Haas AJ, Vepa Y, Lindqvist D, Chen H, Thomas PM, Brundin P, Brundin L, Labrie V. The vermiform appendix impacts the risk of developing Parkinson's disease. Sci Transl Med. 2018 Oct 31;10(465) PubMed.
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